The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents.
Anders M., Tuma I., Rösslerova H. ( 2008) A surveillance study of escitalopram treatment of depressed patients. Expert OpinPharmaco9: 1-6.
2.
Ariens EJ, Soudijn W., Timmermans Pbhwh ( 1983) Stereochemistry and Biological Activity of Drugs . Oxford: Blackwell.
3.
Baldwin DS, Cooper JA, Huusom AK, Hindmarch I. ( 2006) A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder . Int Clin Psychopharm21: 159-169.
4.
Baldwin DS, Reines EH, Guiton C., Weiller E. ( 2007) Escitalopram therapy for major depression and anxiety disorders. Ann Pharmacother41: 1583-1592.
5.
Baumann P., Zullino DF, Eap CB ( 2002) Enantiomers’ potential in psychopharmacology - a critical analysis with special emphasis on the antidepressant escitalopram . Eur Neuropsychopharm12: 433-444.
6.
Bech P., Andersen HF, Wade A. ( 2006) Effective dose of escitalopram in moderate versus severe DSM-IV major depression. Pharmacopsychiatry39: 128-134.
7.
Bielski RJ, Ventura D., Chang CC ( 2004) A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. J Clin Psychiat65: 1190-1196.
8.
Blier P. ( 2003) The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharm13: 57-66.
9.
Blier P., Bouchard, C. ( 1994) Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs. Brit J Pharmacol113: 485-495.
10.
Bose A., Li D., Gandhi C. ( 2008) Escitalopram in the acute treatment of depressed patients aged 60 years or older. Am J Geriat Psychiat16: 14-20.
11.
Boulenger JP, Huusom AK, Florea I., Baekdal T., Sarchiapone M. ( 2006) A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients . Curr Med Res Opin22: 1331-1341.
12.
Brittain RT, Drew GM, Levy GP ( 1982) The alpha- and beta-adrenoceptor blocking potencies of labetalol and its individual stereoisomers in anaesthetized dogs and in isolated tissues. Brit J Pharmacol77: 105-114.
13.
Burke WJ, Gergel I., Bose A., et al. (2002) Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiat63: 331-336.
14.
Chen F., Larsen MB, Neubauer HA, Sanchez C., Plenge P., Wiborg O. ( 2005) Characterization of an allosteric citalopram-binding site at the serotonin transporter. J Neurochem92: 21-28.
15.
Cipriani A., Furukawa TA, Salanti G., et al. (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet373: 746-758.
16.
Clayton AH, Croft HA, Horrigan JP, et al. (2006) Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiat67: 736-746.
17.
Clayton AH, Kornstein SG, Prakash A., Mallinckrodt C., Wohlreich MM ( 2007) Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med4: 917-929.
18.
Colonna L., Andersen HF, Reines EH ( 2005) A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder. Curr Med Res Opin21: 1659-1668.
19.
CONSORT group (2009) CONSORT Statement. Available at: http://www.consort-statement.org/ (accessed 30 March 2009).
20.
Cordato DJ, Mather LE, Herkes GK ( 2003) Stereochemistry in clinical medicine: a neurological perspective . J Clin Neurosci10: 649-654.
21.
Cremers TIFH, Westerink BHC ( 2003) Pharmalogical difference between escitalopram and citalopram . Int J Psychiat Clin7: 306.
22.
Croom KF, Plosker GL ( 2003) Escitalopram: a pharmacoeconomic review of its use in depression. Pharmacoeconomics21: 1185-1209.
23.
Croom KF, Plosker GL ( 2004) Spotlight on the pharmacoeconomics of escitalopram in depression. CNS Drugs18: 469-473.
24.
Davey Smith G., Egger M. ( 1998) Meta-analysis. Unresolved issues and future developments . BMJ316: 221-225.
25.
Davis DA, Thomson MA, Oxman AD, Haynes RB ( 1995) Changing physician performance. A systematic review of the effect of continuing medical education strategies. JAMA274: 700-705.
26.
Demyttenaere K., Andersen HF, Reines EH ( 2008) Impact of escitalopram treatment on Quality of Life Enjoyment and Satisfaction Questionnaire scores in major depressive disorder and generalized anxiety disorder. Int Clin Psychopharm23: 276-286.
27.
Demyttenaere K., Hemels ME, Hudry J., Annemans L. ( 2005) A cost-effectiveness model of escitalopram, citalopram,and venlafaxine as first-line treatment for major depressive disorder in Belgium . Clin Ther27: 111-124.
28.
Egger M., Smith GD ( 1998) Bias in location and selection of studies. BMJ316: 61-66.
29.
Einarson TR ( 2004) Evidence based review of escitalopram in treating major depressive disorder in primary care. Int Clin Psychopharm19: 305-310.
30.
El Mansari M., Sanchez C., Chouvet G., Renaud B., Haddjeri N. ( 2005) Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology30: 1269-1277.
31.
El Mansari ME, Wiborg O., Mnie-Filali O., Benturquia N., Sánchez C., Haddjeri N. ( 2007) Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int J Neuropsychop10: 31-40.
32.
Fantino B., Moore N., Verdoux H., Auray JP ( 2007) Cost-effectiveness of escitalopram vs. citalopram in major depressive disorder. Int Clin Psychopharm22: 107-115.
33.
Fernandez JL, Montgomery S., Francois C. ( 2005) Evaluation of the cost effectiveness of escitalopram versus venlafaxine XR in major depressive disorder. Pharmacoeconomics23: 155-167.
34.
Food and Drug Administration (1992) FDA’s policy statement on the development of new stereoisomeric drugs (steromeric drug policy). Federal Register57: FR22249.
35.
Food and Drug Administration (2002) http://www.fda.gov/cder/foi/nda/2002/21-323_Lexapro.htm (accessed January 2009).
36.
François C., Toumi M., Aakhus AM, Hansen K. ( 2003) A pharmacoeconomic evaluation of escitalopram, a new selective serotonin reuptake inhibitor. Comparison of cost-effectiveness between escitalopram, citalopram, fluoxetine, and venlafaxine for the treatment of depression in Norway. Eur J Health Econ4: 12-19.
37.
Gorman JM, Korotzer A., Su G. ( 2002) Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums7: 40-44.
38.
Gorwood P., Weiller E., Lemming O., Katona C. ( 2007) Escitalopram prevents relapse in older patients with major depressive disorder. Am J Geriat Psychiat15: 581-593.
39.
Hemels ME, Kasper S., Walter E., Einarson TR ( 2004) Cost-effectiveness of escitalopram versus citalopram in the treatment of severe depression. Ann Pharmacother38: 954-960.
40.
Hyttel J., Bogeso KP, Perregaard J., Sanchez C. ( 1992) The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer. J Neural Transm. General Section88: 157-160.
41.
Kasper S., Baldwin DS, Larsson Lonn S., Boulenger JP ( 2009) Superiority of escitalopram to paroxetine in the treatment of depression. Eur Neuropsychopharm19: 229-237.
42.
Kasper S., de Swart H., Andersen Friis H. ( 2005) Escitalopram in the treatment of depressed elderly patients . Am J Geriat Psychiat13: 884-891.
43.
Kasper S., Spadone C., Verpillat P., Angst J. ( 2006a) Escitalopram in the long-term treatment of major depressive disorder in elderly patients. Neuropsychobiology54: 152-159.
44.
Kasper S., Spadone C., Verpillat P., Angst J. ( 2006b) Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharm21: 105-110.
45.
Kennedy SH, Andersen HF, Lam RW ( 2006) Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J Psychiatr Neurosci31: 122-131.
46.
Kennedy SH, Andersen HF, Thase ME (2009) Escitalopram in the treatment of major depressive disorder: a meta-analysis. Curr Med Res Opin25: 161-175.
47.
Khan A., Bose A., Alexopoulos GS, Gommoll C., Li D., Gandhi C. ( 2007) Double-blind comparison of escitalopram and duloxetine in the acute treatment of major depressive disorder. Clin Drug Invest27: 481-492.
48.
Klein N., Sacher J., Geiss-Granadia T., et al. (2007) Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study. Psychopharmacology191: 333-339.
49.
Kornstein SG, Bose A., Li D., Saikali KG, Gandhi C. ( 2006) Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. J Clin Psychiat67: 1767-1775.
50.
Kornstein SG, Li D., Mao Y., Larsson S., Andersen HF, Papakostas GI ( 2009). Escitalopram versus SNRI antidepressants in the acute treatment of major depressive disorder: integrative analysis of four double-blind, randomized clinical trials. CNS Spectr14: 326-33.
51.
Kulp W., von der Schulenburg JM, Greiner W. ( 2005) Cost-effectiveness of outpatient treatment in depressive patients with escitalopram in Germany. Eur J Health Econ6: 317-321.
52.
Lader M., Andersen HF, Baekdal T. ( 2005) The effect of escitalopram on sleep problems in depressed patients. Hum Psychopharm20: 349-354.
53.
Lam RW, Andersen HF ( 2006) The influence of baseline severity on efficacy of escitalopram and citalopram in the treatment of major depressive disorder: an extended analysis. Pharmacopsychiatry39: 180-184.
54.
Lam RW, Andersen HF, Wade AG ( 2008) Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials. Int Clin Psychopharm23: 181-187.
55.
Lam RW, Annemans L. ( 2007) Efficacy, effectiveness and efficiency of escitalopram in the treatment of major depressive and anxiety disorders. Expert Rev Pharmacoecon & Outcomes Res7: 559-576.
56.
Lancon C., Sapin C., Note I., Farisse J. ( 2006) Comparison of escitalopram and citalopram in outpatients with severe major depressive disorder: a prospective, naturalistic, 8-week study. Int J Psychiat Clin10: 131-137.
57.
Leonard BE ( 2001) An introduction to enantiomers in psychopharmacology . Hum Psychopharm16: S79-S84.
58.
Lepola U., Wade A., Andersen HF ( 2004) Do equivalent doses of escitalopram and citalopram have similar efficacy? A pooled analysis of two positive placebo-controlled studies in major depressive disorder. Inte Clin Psychopharm19: 149-155.
59.
Lepola UM, Loft H., Reines EH ( 2003) Escitalopram (10-20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Inte Clin Psychopharm18: 211-217.
60.
Lieberman JA, Greenhouse J., Hamer RM, et al. (2005) Comparing the effects of antidepressants: Consensus guidelines for evaluating quantitative reviews of antidepressant efficacy. Neuropsychopharmacology30: 445-460.
61.
Llorca PM, Azorin JM, Despiegel N., Verpillat P. ( 2005) Efficacy of escitalopram in patients with severe depression: a pooled analysis. Int J Clin Prac59: 268-275.
62.
Llorca PM, Fernandez JL ( 2007) Escitalopram in the treatment of major depressive disorder: clinical efficacy, tolerability and cost-effectiveness vs. venlafaxine extended-release formulation. Int J Clin Prac61: 702-710.
63.
Lucki I., Brown K. ( 2003) Different roles of the enantiomers of citalopram on serotonin transmission. Biol Psychiat53: 45S.
64.
Mao PX, Tang YL, Jiang F., et al. (2008) Escitalopram in major depressive disorder: a multicenter, randomized, double-blind, fixed-dose, parallel trial in a Chinese population. Depress Anxiety25: 46-54.
65.
McConathy J., Owens MJ ( 2003) Stereochemistry in drug action. Prim Care Companion J Clin Psychiat5: 70-73.
66.
Meyer JH, Wilson AA, Sagrati S., et al. (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiat161: 826-835.
67.
Moller HJ, Langer S., Schmauss M. ( 2007) Escitalopram in clinical practice: results of an open-label trial in outpatients with depression in a naturalistic setting in Germany . Pharmacopsychiatry40: 53-57.
68.
Montgomery SA, Andersen HF ( 2006) Escitalopram versus venlafaxine XR in the treatment of depression. Int Clin Psychopharm21: 297-309.
69.
Montgomery SA, Huusom AK, Bothmer J. ( 2004) A randomised study comparing escitalopram with venlafaxine XR in primary care patients with major depressive disorder. Neuropsychobiology50: 57-64.
70.
Moore N., Verdoux H., Fantino B. ( 2005) Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharm20: 131-137.
71.
Mørk A., Kreilgaard M., Sanchez C. ( 2003) The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats . Neuropharmacology45: 167-173.
72.
National Health Service (2009) 10 questions to help you make sense of randomised controlled trials. Available at: http://www.phru.nhs.uk/Doc_Links/rct%20appraisal%20tool.pdf (accessed 30 March 2009).
73.
Nemeroff C., Entsuah, R., Benattia I., Demitrack M., Sloan, DM, Thase, ME ( 2008) Comprehensive analysis of remission (COMPARE) with venlafaxine XR versus SSRIs. Biol Psychiat63: 424-434.
74.
Nierenberg AA, Greist JH, Mallinckrodt CH, et al. (2007) Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study. Curr Med Res Opin23: 401-416.
75.
Overo K. ( 1982) Kinetics of citalopram in man; plasma levels in patients . Prog Neuro-Psychopha Biol Psychiat6: 311-318.
76.
Papakostas GI, Thase ME, Fava M., Nelson JC, Shelton RC ( 2007) Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiat62: 1217-1227.
77.
Pedersen AG ( 2005) Escitalopram and suicidality in adult depression and anxiety . Int Clin Psychopharm20: 139-143.
78.
Pigott TA, Prakash A., Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM ( 2007) Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin23: 1303-1318.
79.
Plenge P., Gether U., Rasmussen SG ( 2007) Allosteric effects of R- and S-citalopram on the human 5-HT transporter: evidence for distinct high- and low-affinity binding sites . Eur J Pharmacol567: 1-9.
80.
Rapaport MH, Bose A., Zheng H. ( 2004) Escitalopram continuation treatment prevents relapse of depressive episodes. J Clin Psychiat65: 44-49.
81.
Rosenbaum JF ( 2001) Introduction: early onset of antidepressant action . J Clin Psychiat62(Suppl 4): 3.
82.
Rush AJ, Bose A. ( 2005) Escitalopram in clinical practice: results of an open-label trial in a naturalistic setting. Depress Anxiety21: 26-32.
83.
Sanchez C. ( 2003) R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model. Eur J Pharmacol464: 155-158.
84.
Sanchez C. ( 2006) The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol99: 91-95.
85.
Sanchez C., Bergqvist PB, Brennum LT, et al. (2003a) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology167: 353-362.
86.
Sanchez C., Bogeso KP, Ebert B., Reines EH, Braestrup C. ( 2004) Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology174: 163-176.
87.
Sanchez C., Gruca P., Bien E., Papp M. ( 2003b) R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol, Biochem and Behavior75: 903-907.
88.
Sidhu J., Priskorn M., Poulsen M., Segonzac A., Grollier G., Larsen F. ( 1997) Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality9: 686-692.
89.
Smith D., Dempster C., Glanville J., Freemantle N., Anderson I. ( 2002) Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis . Brit J Psychiat180: 396-404.
90.
Sorensen J., Stage KB, Damsbo N., Le Lay A., Hemels ME ( 2007) A Danish cost-effectiveness model of escitalopram in comparison with citalopram and venlafaxine as first-line treatments for major depressive disorder in primary care. Nord J Psychiat61: 100-108.
91.
Svensson S., Mansfield PR ( 2004) Escitalopram: superior to citalopram or a chiral chimera ? Psychother Psychosom73: 10-16.
92.
Tanum L., Strand LP, Refsum H. ( 2003) S- and R-citalopram ratio in patients treated with racemic citalopram on different dose-levels. Nord J Psychiat57: 109.
93.
Taylor D., Stewart S., Connolly A. ( 2006a) Antidepressant withdrawal symptoms - telephone calls to a national medication helpline. J Affect Disorders95: 129-133.
94.
Taylor MJ, Freemantle N., Geddes JR, Bhagwagar Z. ( 2006b) Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiat63: 1217-1223.
95.
Thase M. ( 1999) How should efficacy be evaluated in randomized clinical trials of treatments for depression? J Clin Psychiat60(Suppl 4): 23-31.
96.
Thase M. ( 2008) Are SNRIs more effective than SSRIs? A review of the current state of the controversy. Psychopharmacol Bull41: 58-85.
97.
Thase ME ( 2002) Comparing the methods used to compare antidepressants . Psychopharmacol Bull36(Suppl 1): 1-19.
98.
Thase ME, Entsuah AR, Ahmed S., Sloan DM ( 2005) Meta-analysis of randomized controlled trials comparing venlafaxine XR and SSRIs: the evidence revisited. In: American Psychiatric Association Annual Meeting, Atlanta, GA, USA.
99.
Ventura D., Armstrong EP, Skrepnek GH, Haim Erder M. ( 2007) Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial. Curr Med Res Opin23: 245-250.
100.
Wade A., Despiegel N., Heldbo Reines E. ( 2006) Escitalopram in the long-term treatment of major depressive disorder. Ann Clin Psychiat18: 83-89.
101.
Wade A., Friis Andersen H. ( 2006) The onset of effect for escitalopram and its relevance for the clinical management of depression. Curr Med Res Opin22: 2101-2110.
102.
Wade A., Gembert K., Florea I. ( 2007) A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder. Curr Med Res Opin23: 1605-1614.
103.
Wade A., Michael Lemming O., Bang Hedegaard K. ( 2002) Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharm17: 95-102.
104.
Wade AG, Fernández JL, François C., Hansen K., Danchenko N., Despiegel N. ( 2008) Escitalopram and duloxetine in major depressive disorder: a pharmacoeconomic comparison using UK cost data. Pharmacoeconomics26: 969-981.
105.
Wade AG, Toumi I., Hemels ME ( 2005a) A pharmacoeconomic evaluation of escitalopram versus citalopram in the treatment of severe depression in the United Kingdom . Clin Ther27: 486-496.
106.
Wade AG, Toumi I., Hemels ME ( 2005b) A probabilistic cost-effectiveness analysis of escitalopram, generic citalopram and venlafaxine as a first-line treatment of major depressive disorder in the UK. Curr Med Res Opin21: 631-642.
107.
Waldeck B. ( 2003) Three-dimensional pharmacology, a subject ranging from ignorance to overstatements. Pharmacol Toxicol93: 203-210.
108.
Wu E., Greenberg PE, Yang E., Yu A., Erder MH ( 2008) Comparison of escitalopram versus citalopram for the treatment of major depressive disorder in a geriatric population. Curr Med Res Opin24(9): 2587-2595.
109.
Yevtushenko VY, Belous AI, Yevtushenko YG, Gusinin SE, Buzik OJ, Agibalova TV ( 2007) Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients. Clin Ther29: 2319-2332.
